2025-09-25

The Variabilities of Dopamine (₯) - PART IX: Serotonin, a friend and foe, going or waiting? MeSH:D012701

 

Historically, research on cognitive behavior has focused on dopamine’s role in learning and memory, particularly through associative learning, linking stimuli (causes) to specific outcomes. Dopamine was believed to capture the core multicellular biological processes underlying neurobehavior. However, recent scientific advances have revealed that serotonin(5-hydroxytryptamine; 5HT), which interacts antagonistically with dopamine, plays a crucial role in shaping this picture. 

To understand their relationship, we begin with a brief overview using the National Library of Medicine’s Medical Subject Headings (MeSH) knowledge tree. Figure 2 illustrates the MeSH classification for dopamine (MeSH:D004298 or ChEBI:18243) and serotonin (MeSH:D012701 or ChEBI:28790). Both are monoamines, with serotonin descending from the tryptamine family. A deeper exploration of serotonin’s classification via the Chemical Entities of Biological Interest (ChEBI) will be provided in a future article.

One long-standing theory in neuroscience, the opponency hypothesis, proposes that two systems encode emotional events: one for positive (appetitive) responses and another for negative (aversive) ones. These systems inhibit each other or exert opposing effects on shared outputs. Physiologically, this model compensates for the absence of negative affect. In this framework, dopamine drives immediate action, while serotonin promotes patience, dopamine encourages behavior, serotonin inhibits it, helping organisms weigh risks and rewards. 


Another theory, the synergy hypothesis, suggests that dopamine handles short-term rewards while serotonin manages long-term benefits. This model integrates dopamine’s role in temporal-difference learning with serotonin’s influence on emotional regulation. Despite their appeal, both hypotheses have been difficult to verify due to limitations in manipulating multiple neuromodulatory systems within individual subjects.

A breakthrough study from Stanford University, “Opponent control of reinforcement by striatal dopamine and serotonin,” introduced a novel experimental model that directly validates the antagonistic and synergistic roles of these neurotransmitters. Researchers developed a genetic strategy to simultaneously access dopamine and serotonin systems in the same mouse. By labeling dopamine and serotonin neurons with distinct fluorescent proteins, they identified the posterior-medial nucleus accumbens (NAc) as a convergence point for both signals.

During reward-learning tasks, dopamine levels increased while serotonin levels decreased when mice received a reward. Using optogenetics to selectively block or stimulate each system, researchers found that disabling both systems impaired learning entirely. Conversely, simultaneous dopamine stimulation and serotonin inhibition enhanced learning more than dopamine stimulation alone.

Replicating these findings in the nucleus accumbens confirmed that dopamine and serotonin act in opposition yet synergistically to support reward learning. The study likens their interaction to a car’s accelerator and brake: dopamine signals “go” when outcomes exceed expectations, while serotonin signals “stop” or “wait,” encouraging long-term consideration over impulsive action.

Clinically, this insight opens new possibilities. Addiction treatments might benefit from dampening dopamine while boosting serotonin, whereas depression therapies could aim to enhance both systems to improve motivation and planning.

In essence, effective learning depends on the interplay between dopamine’s drive and serotonin’s restraint. As you read this, these neurotransmitters are shaping your brain’s reward-learning mechanisms: balancing action and inhibition to help you navigate opportunities wisely.

 

REFERENCE

  • MeSH:D004298; ChEBI:18243; MeSH:D012701; ChEBI:28790
  • Cardozo Pinto, D. F., Pomrenze, M. B., Guo, M. Y., Touponse, G. C., Chen, A. P., Bentzley, B. S., ... & Malenka, R. C. (2024). Opponent control of reinforcement by striatal dopamine and serotonin. Nature, 1-3.
  • Weiler, N. Dopamine and serotonin work in opposition to shape learning, Neuroscience News, Stanford University. Nov 25 2024.
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